The genes of the Hox clusters have intrigued scientists for decades due to their role in patterning the body plan, their physical proximity and the phenomenon of their sequential gene expression known as colinearity. Recent work has shown that dynamic modulation of chromatin structure plays an indispensable role in the regulation of these genes. For instance, Polycomb complexes methylate H3 K27 to repress Hox expression while MLL and Trithorax methylate H3 K4 to activate transcription. The roles of ATP dependent chromatin remodeling complexes in controlling Hox gene expression are less understood. These complexes remodel chromatin by utilizing ATP to modulate nucleosome position. Several lines of evidence suggest that the Swi/Snf chromatin-remodeling complex plays an integral role in regulation of Hox genes. Drosophila Brahma, an ATPase and core component of the Swi/Snf complex, was repeatedly isolated from a screen for factors that regulate Hox gene expression. Recently, we have found Snf5, another core component of the Swi/Snf complex, is specifically required for Hox gene expression in murine embryonic fibroblasts. Lastly, multiple groups have shown that Snf5 physically interacts with MLL and its Drosophila homolog Trithorax, both of which positively regulate Hox gene expression. Intriguingly, translocations of MLL are frequently found in acute leukemias and inactivating mutations of Snf5 lead to aggressive pediatric cancers and are the basis of a familial cancer syndrome. In fact, dysregulation of Hox gene expression is thought to contribute to the genesis of numerous types of cancer. The experiments in this proposal will test the hypothesis that Snf5 plays a critical role in the regulation of clustered Hox gene expression and that this regulation is facilitated by interactions with MLL. By elucidating the role of Snf5 in MLL-mediated activation of Hox genes and by identifying the mechanistic basis of Hox gene regulation by Snf5, the results of these experiments will delineate the role of Swi/Snf in Hox gene expression and will provide a framework for understanding the chromatin-based regulation of gene expression. Since MLL and Snf5 are both mutated in human cancers, generating insight into their roles in gene regulation and transformation may identify novel targets for therapeutic intervention to these lethal cancers.